Abdominal aortic aneurysms (AAAs) cause 1-3% of all deaths among men between the ages of 65-85 in developed nations. The condition is characterized by chronic enzymatic disruption and progressive loss of the extracellular matrix (ECM), particularly the elastic matrix, within the wall of the infrarenal abdominal aorta, leading to its slow expansion and weakening, to culminate in fatal rupture. (Selle et al., Ann Surg. 189:158-64 (1979)). The matrix metalloproteinases (MMPs)-2 and -9, which are overexpressed by inflammatory cells recruited to the AAA site, as well as activated aortic smooth muscle cells (SMCs) at the AAA site, have been shown to cause elastin breakdown, thereby driving AAA growth. (Daugherty A, Cassis L A., Curr Atheroscler Rep. 4:222-7 (2002)). Unfortunately, auto-repair and/or regeneration of elastic matrix by adult vascular cells, and more so diseased aneurysmal cells, is very poor. Additionally, since they are incapable of efficiently recruiting, crosslinking and organizing elastin precursors into a mature fiber-based matrix, reversal of AAA pathology is not possible. This prospect is also further diminished by the apoptosis of SMCs within the elastic medial layer of the aorta, and the chronic overexpression of MMPs due to which net accumulation of the limited de novo synthesized elastic matrix is poor.
Greater than 90% of AAAs in humans tend to be detected when they are still small (i.e., their maximal diameter is less than 5.5 cm), and have a slow growth rate (<10% per year). However, they tend to be surgically or minimally invasively treated only when they attain a size greater than 5.5 cm, when they have high risk of rupture. (Lederle et al., Arch Intern Med.; 160:1425-30 (2000)). Since many elderly patients are unfit for surgery, there is a strong but unmet need for pathophysiologically-based non-surgical therapies that may be applied during the >5 years passive monitoring of small, growing AAAs, before they attain a size at which the rupture risk outweighs the surgical risk.
An intraluminal thrombus (ILT) is present in ˜75% of all AAAs, and is a critical pathophysiological determinant of AAA growth, although its exact role in AAA progression has remained contradictory. While some studies have suggested that the ILT is ‘inert’ and shields the underlying wall from hemodynamic stresses, others have shown it to mediate proteolytic changes in the aortic wall that lead to AAA growth and rupture. (Vorp et al., J Vasc Surg. 34:291-9 (2001)). Additionally, studies have shown a strong correlation between ILT size, AAA growth, and the risk of rupture, leading to its recognition as an important indicator of AAA progression. (Stenbaek et al., European Journal of Vascular and Endovascular Surgery. 20:466-9 (2000)). Based on the varied roles of the ILT in AAA progression and its likely impediment to the diffusion of oxygen and delivered therapeutics from the bloodstream into the AAA wall, there is a critical need to develop approaches to render the clots porous or to lyse them. Thrombolysis following intravenous administration of tissue plasminogen activator (tPA) has been shown to be effective in rapidly restoring blood flow in patients following thrombotic events such as stroke (Shaltoni et al., Stroke, 38:80-4 (2007)) and myocardial infarction (MI) (Chesebro et al., Circulation. 76:142-54 (1987). It converts plasminogen in the bloodstream into its active plasmin form, which then circulates systemically and mediates thrombolysis. However, high systemic plasmin levels lead to enhanced MMP expression (Lijnen H R, Thromb Haemost. 86:324-33 (2001)) and elastin/elastic matrix degradation (Chen et al., J Control Release. 118:65-77 (2007)), which are undesirable in an AAA scenario. Additionally, rapid clot lysis may be undesirable from the standpoints of (a) sudden exposure of the underlying aortic wall to proteases and inflammatory cells present in the ILT, and (b) loss of its (bio)mechanical shielding effect on the underlying wall. Therefore, there is a critical need for methods to enable slow and controlled thrombolysis to modulate plasmin production, minimize systemic plasminemia, and prevent AAA rupture.
On account of systemic plasminemia associated with systemic delivery and doses of plasminogen activators, studies have examined the development of nanoparticle (NP)-based controlled release systems. This is due to the fact that tPA also acts upon plasminogen in circulation generating systemic plasmin and rendering the treated patient highly vulnerable to hemorrhage. Newer products that have been developed such as micro- and nanoscale devices for delivery of active fibrinolytic agents focus on delivering tPA to a blood clot for postmyocardial infarction or ischemic stroke treatment using nanoparticles. See PCT publication WO/2009/052367. These fibrinolytic nanoparticles attempt to minimize systemic plasminemia compared to the use of free tPA. However, these nanoparticle delivery systems can still result in rapid and relatively uncontrolled lysis of the clot.